Inhibition of GSK-3 Induces Differentiation and Impaired Glucose Metabolism in Renal Cancer

Abstract

Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases including Type II diabetes, Alzheimer's disease, bipolar disorder, inflammation and cancer. Consequently it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacological and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent anti-proliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The anti-proliferative activity is most likely caused by G0–G1 and G2-M phase arrest as evident from cell cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. Additionally, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft RCC tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells.

GSK-3 inhibition overcomes chemoresistance in human breast cancer

“…Our in vitro results demonstrate that 9-ING-41 is a more potent inhibitor of breast cancer cell growth than other available GSK-3 inhibitors including the clinical stage compound LY2090314. We demonstrate that inhibition of GSK-3 by 9-ING-41 decreases the survival of breast cancer cells in vitro , consistent with previously published studies in other tumor cell types [11–22,25,32–36]. Our previous studies in leukemic cells showed that the inhibition of GSK-3 using a toolkit inhibitor suppressed NF-κB transcriptional activity and decreased the expression of the antiapoptotic proteins (XIAP, Bcl-2), leading to enhaced cancer cell apoptosis [15].…”

“…Moreover, breast cancer patients with GSK-3β expression in the highest quartile (246 of 1686 cases) had a 2.7 and 1.7-fold increased risk of distant relapse 5 and 10 years after tumor resection, respectively [23]. In the present study, we describe a novel GSK-3 inhibitor 9-ING-41 which shows robust antitumor activity in vitro and in vivo and possesses drug-like properties [13,25,32]. Our in vitro results demonstrate that 9-ING-41 is a more potent inhibitor of breast cancer cell growth than other available GSK-3 inhibitors including the clinical stage compound LY2090314.…”

Molecular Pathways: Revisiting Glycogen Synthase Kinase-3β as a Target for the Treatment of Cancer

“…These results support the hypothesis that targeting GSK-3 can overcome chemoresistance in human breast cancer, and credentialed 9-ING-41 as a novel GSK-3 targeted agent for the treatment of metastatic breast cancer. Consistent with the results in breast carcinoma models, 9-ING-41 antitumor activity has been demonstrated in ovarian, pancreatic and renal cancer models in vitro and in vivo and initial DMPK and toxicology studies support advancing this molecule into clinical translation (26, 60, 63). …”

Combination Treatment with the GSK-3 Inhibitor 9-ING-41 and CCNU Cures Orthotopic Chemoresistant Glioblastoma in Patient-Derived Xenograft Models

“…These data provide a rationale for evaluating the activity of 9-ING-41, a small molecule inhibitor of GSK-3β, as a novel therapeutic for GBM. Previous studies have demonstrated the antitumor activity and drug-like properties of this compound, including good tolerability at therapeutic doses in tumor-bearing rodents [15], [16], [17], [18]. The two isoforms of GSK-3, α and β, are 98% homologous, and known competitive inhibitors of GSK-3β, including 9-ING-41, inhibit both isoforms [15], [17], [19].…”